Substituted, 6,7 ethylenedioxy 4 hydroxy 3 non oxo carbonylic quinolines

ABSTRACT

Compounds of the formula 1 have potent diuretic and saluretic effects and a very low toxicity. The compounds can be synthesized by usual methods and be given suitable forms for administration and be used for the treatment of inter alia edemas. The compounds are novel.

a United States Patent Boschman et al.

SUBSTITUTED, 6,7 ETHYLENEDIOXY 4 HYDROXY 3 NON 0X0 CARBONYLIC QUINOLINESinventors: Theodorus Antonius Cornelis Boschman; Jacob Gerard Korsloot,both of van Houteniaan.

Netherlands Assignee: U.S. Philips Corporation, New

York, NY.

Filed: Feb. 5, 1973 Appl. No.: 329,692

Foreign Application Priority Data Feb. 9, 1972 Netherlands 7201675 Nov.14, 1972 Netherlands 7215366 U.S. Cl. 260/287 R, 260/283 CN, 260/283 SY,260/283 S, 260/288 R, 260/289 R, 260/340.3, 424/258 Int. Cl C07d 33/48Field of Search 260/287 R [56] References Cited UNITED STATES PATENTS3,178.348 4/1966 Bickerton 260/287 R 3,287,458 11/1966 Kaminsky 260/287R 3.761.482 9/1973 Nakagome 260/287 R FOREIGN PATENTS OR APPLICATIONS1.240.316 7/1971 Great Britain 260/287 4/1971 France 260/287 PrimaryExaminer-Donald G. Daus Assistant ExaminerD. Wheeler Attorney, Agent, orFirmFrank R. Trifari; Norman N. Spain [57] ABSTRACT Compounds of theformula 1 have potent diuretic and saluretic effects and a very lowtoxicity. The compounds can be synthesized by usual methods and be givensuitable forms for administration and be used for the treatment of interalia edemas. The compounds are novel.

35 Claims, 22 Drawing Figures SUBSTITUTED, 6,7 ETHYLENEDIOXY 4 HYDROXY 3NON OX CARBONYLIC QUINOLINES The invention relates to novel quinolinederivatives having pharmacological effects.

A large number of quinoline derivatives are described, inter alia, inBelgian Pat. No. 725,787. Antibacterial and coccidiostatic properties ofthe known compounds have been described.

It was found that the compounds of the formula I have a strong diureticand saluretic effect.

In formula I the symbols have the following meanings:

R, is either a group where R is an alkoxy or dialkylaminoalkoxy group,an alkoxyalkyloxy, alkenyloxy, cycloalkoxy or cycloalkylalkoxy groupcontaining at most 4 C atoms, but if R denotes a halogen atom or a CF;;group, ,at most 6 C atoms, a hydroxy group, an amino group, a hydrogenatom or an alkyl group containing at most 3 C atoms,

or a group CHR OR where R is a hydrogen atom or an acyl group containingfrom 2 to 4 C atoms and R, is a hydrogen atom or an alkyl groupcontaining at most 3 C atoms,

or an alkyl group containing at most 4 C atoms;

R represents either a group (CH 0R where R, is a hydrogen atom, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkoxyalkyl ortetrahydrofuranalkyl group containing at most 6 C atoms, an acyl groupcontaining from 2 to 4 C atoms, a phenylalkyl group containing up to 8 Catoms or a dialkylaminoalkyl group, whilst n is 1 or 2,

or a group (CH S(O),,,R,,, where R, represents an alkyl group containingfrom I to 3 C atoms, m is O, lor2andnislor2;

R is a hydrogen atom or a halogen atom, an alkyl or alkoxy groupcontaining at most 4 C atoms, a trifluoromethyl group, a nitro or aminogroup, an acylamino group containing up to 4 C atoms, a cyano or ahydroxy group;

and R represents a hydroxy or mercapto group, an alkoxy or alkylthiogroup containing at most 3 C atoms or, if R represents a halogen atom ora trifluoromethyl group, a chlorine or bromine atom.

The said compounds include the alkali metal salts of the carboxyl groupR, and the acid addition salts formed with pharmaceutically acceptableacids. The term alk(en)yl (oxy) groups denotes both straightchain andbranched-chain groups.

Because the compounds contain an asymmetric carbon atoms, the formula Idenotes both racemates andenantiomers. The compounds in which Rrepresents a hydroxy group or a mercapto group are tautomeric with thecompounds of the formula 1a in which X represents an oxygen atom or asulphur atom. The equilibrium is greatly shifted towards the structureof formula 1a. Hence compounds of the formula la also are considered asfalling within the scope of the invention.

The fact that compounds of the formula have diuretic properties is themore surprising because the known compounds have no diuretic effects.

- The following Table shows the result of a diruetic test Compound ofthe Dose mg/kg Oral Increase in Volume Formula of Urine in Per Cent Ifin the compound of the formula 2a a chlorine atom is introduced at theposition 10, a compound is obtained that is about times more potent.

The compounds of the formula have a strong diuretic effect showing ahigh ceiling. Unlike the commonly used diuretic furosemide(4-chloro-5-sulfamoyl-N-(furyl-2-methyl) anthranilic acid) the compoundshave a dose-effect relation which varies very gradually. As a result,the compounds may readily be used and in spite of individual differencesin sensitivity between patients they may be admdinistered without therisk of excessive or insufficient effect of the dose administered.

The diuretic effect is accompanied by a saluretic effect which mainlyshows itself as a strong increase in the excretion of sodium ions,whereas the increase of the excretion of potassium ions is much smaller.

In renally hypertensive rats the compounds cause a fall in bloodpressure after repeated administration.

The toxicity of the compounds is very small. For example, in the mouseon oral administration the compound of the formula 2a has a LD of 4,080mg/kg, the compound of formula 2b a [D of 1,000 mg/kg. Even afterrepeated administration no infulence on the blood sugar content isfound.

The compounds may be used for treating hypertension, cardiac asthma,decompensation of the heart, pulmonary edema, hepatic edema withascites, nephrogenous edema, cardiac edema, pregnancy edema, lymphatic,edema, iodopathic edema, edema in adiposis, post-traumatic edema,medicamentous edema, edema in malignant diseases, premenstrual tension,nephrotic syndrome, gestational teoxicosis, barbiturate intoxica' tion,inhibition of lactation and renal and central diabetes insipidus.

The doses in which, the frequency at which and the route by which thecompounds are administered depend upon the nature and the seriousness ofthe diseases for the treatment of which they are used. In general adaily dose of from 0.5 mg to 200 mg will be sufficient.

The compounds of the formula 1 in which R represents a hydroxyl group, Ran alkoxycarbonyl, alkoxyalkoxycarbonyl, carboxyl, alkylcarbonyl orhydfoxymethyl group, R is an alkoxyalkyl or an alkoxyalkoxyalkyl groupand R is a hydrogen atom, a halogen atom, a trifluoromethyl group or anitro group, have particularly strong diuretic effects. Among thesecompounds particularly, those in which R represents a halogen atom haveare particularly potent.

The diuretic effect of the compounds was determined in the testarrangement described by Lipschitz, Hadidian and Kerpcsar, J. Pharm.exptl. Therap. 79, 97-l10 (1943), with a few small modifications Thecompounds to be tested were suspended in an aqueous 1 percent by weightsolution of tragacanth in water and orally administered to male rats(weight between 100 g and 200 g) which were fasted for 18 hours.Immediately after the adminstration of the substance they were orallygiven 2.5 ml of physiological salt solution per 100 g of body weight.The animals were put in metabolism cages in which urine and faeces couldbe collected separately. The urine was collected in graduated 'vessels,and readings of the volume were taken 2% hours and hours afteradministration. The amounts of Na ions, K ions and Cl ions in the urineobtained after 5 hours were determined. The urine volumes and theelectrolyte concentrations of the animals treated with the compoundswere compared with those of control animals.

The compounds of the formula 1 can be obtained by known methods.Accordingly the invention also relates to a method of preparing novelquinoline derivatives which is'characterized in that compounds of theformula l, alkali metal salt, acid addition salts and tautomers thereofare prepared by methods known for the preparation of such compounds andby analogous methods. 4 1

For example, compounds of the formula 1 in which R is an OH group areobtainable in intramolecular condensation of a compound of the formula 4or a tautomer thereof. In this formula the symbols R, to R' have thesame meanings also have R, to R in the formula I, however, hydroxygroups and amino groups now are protected by benzyl, benzyloxycarbonyl,acyl or alkoxycarbonyl groups. R denotes the same group als R, when R,represents a carboxyl group or an esterified carbonyl group, but in allother cases it may also represent a halogencarbonyl group or a groupalklol where alk is a lower alkyl group, for example a methyl group oran ethyl group.

The reaction is carried out at elevated temperature up to most about250C. The reaction may proceed in the melt or in a solution. In thelatter case a highboiling-point solvent, such as diphenyl, diphenylether, mineral oils and the like, may be used, or a condensing agent,such as polyphosphoric acid or an ester thereof, phosphorus oxychloride(POCI phosphorus pentoxide, quinoline, aluminium chloride and the like,and a solvent may be used. In some cases the condensing agent may alsoserve as a solvent. After the condensation reaction the protectedhydroxy and amino groups in R, to R' can be converted into free aminoand hydroxy groups by acid or alkaline hydrolysis. Protective benzyl andbenzyloxycarbonyl groups may also be removed by hydrogenolysis, forexample with Pt or Pd/C and hydrogen under a slightly increasedpressure, for example 1.1 atmospheres.

Compounds of the formula 4 are obtainable by condensing a compound ofthe formula 5, for example in ethanol, with a compound of the formula 6.

The reaction product need not be isolated, but may be converted intocompounds of the formula 1, for example, by adding a high-boiling-pointsolvent and raising the temperature.

The amines of the formula 5 are usually obtained by reducing thecorresponding nitrocompounds, for example with Pd/C and hydrogen.

The compounds of the formula 1 in which R represents a hydroxy group mayalso be obtained by intramolecularly condensing a compound of theformula 7 or a tautomer thereof in which R represents a carboxyl groupor an esterified carboxyl group. This reaction may be carried out in aninert solvent such, for example, as diethyl ether and a base such, forexample, as an alcoholate at temperatures between room temperature andthe boiling point of the mixture. After the condensation reaction freeamino groups and hydroxy groups are obtainable from the protectedhydroxy groups and amino groups in R, to R',, by hydrolysis orhydrogenolysis. The compounds of the formula 7 may be obtained byreacting a compound of the formula 8 with a compound of the formula 9 inan inert solvent, such as ethanol, with heating.

Another method of preparing compounds of the formula l is that in whicha compound of the formula 10 or a tautomer thereof is intramolecularlycondensed. The reaction is carried out in an inert solvent, such as forexample dioxan, in the presence of a catalytic amount of a base, forexample NaOH or KOH. The reaction is performed at temperatures betweenroom temperature and about C. After the condensation reation theprotected hydroxy groups and amino groups in the substituents R, to R'are converted into free amino groups and hydroxy groups by hydrolysis orhydrogenolysis. The compounds of the formula 10 are obtainable byreacting a compound of the formula 1 l with a compound of the formula 12or a tautomer thereof, for example in dioxan, using a base as acatalyst. Compounds of the formula 1 l are obtained by reacting thecorresponding anthranilic acid derivitative with phosgene.

Since compounds of the formula 10 are converted into compounds of theformula 1 under the same conditions under which they are obtained fromcompounds of the formula 11, the starting substances of the formula 10can be prepared in situ.

The compounds of the formula I in which R represents a hydroxy group arealso obtainable by ring closure of a compound of the formula l3 or atautomer thereof in which Hal represents a halogen atom. The reaction iscarried out in an inert solvent such as, for example, water, alcoholssuch as ethanol, ketones such as acetone and methylethylketone,preferably in the presence of a base such, for example, as K CO KOl-l orNaOH. As a rule the reaction temperature is between 50C and 100C. Thecompounds of formula 13 are obtainable, for example, by reacting acompound of the formula 14 with a compound of the formula 15 whilstheating in the presence of a base. Subsequently the group R a benzylgroup or a methoxymethyl group, is split off by acid hydrolysis.

The compounds of the formula l in which R is a hydroxy group and R is ahydroxymethyl group may also be obtained by ring closure of a compoundof the formula 16 or a tautomer thereof, for example in a dilutedaqueous solution of a base, at about 50C to 100C.

The compounds of the formula 16 are obtainable by condensing a compoundof the formula 14 under alkaline conditions with an epihalogenhydrin,subsequent acid hydrolysis to split off the group R and reaction with anaqueous solution of a base.

Compounds of the formula 1 in which R represents a hydroxy group and R,represents a carboxyl group are obtainable by hydrolysing a compound ofthe formula 17. The reaction is preferably carried out with a strongbase in, for example, ethanol or with a strong acid in water attemperatures between room temperature and the boiling point of themixture. The compounds of the formula 17 are obtainable by methodsanalogous to the above described methods.

When a compound of the formula 17 is hydrolysed under mild conditions,carboxylamides of the formula 1 in which R represents a hydroxy groupare obtained. This reaction is usually carried out under acidconditions, for example in a mixture of glacial acetic acid and dilutehydrochloric acid, at room temperature or a slightly elevatedtemperature, for example between 40C and 50C.

The compounds of the formula l in which R represents a hydroxy group andR represents an esterified carboxyl group may be prepared from compoundsof the formula 17 by alcoholysis with the alcohol with which thecarboxyl group is to be esterified. This reaction is carried out underacid conditions at temperatures up to the boiling point of the mixture.The intermediately formed imino esters are decomposed with water.

The compounds of the formula 1 in which R represents a hydroxy group mayalso be obtained by hydrolysing a compound of the formula 18 tosubstitute an oxygenatom for the halogen atom Hal.

The reaction is carried out in an inert solvent such, for example, as analcohol to which a small amount of water has been added. If required themedium may be acidified. The temperature of the mixture is preferablyraised to about 100C to increase the reaction velocity.

The compounds of the formula 18 are obtained by reacting compounds ofthe formula 19 with more than 2 equivalents of a phosphorus oxyhalide.

The carboxylic acids of the formula 1 in which R represents a hydroxygroup may alternatively be obtained in that ina compound of the formula20 in which Hal is a halogen atom and p 3, hydroxy is substituted forhalogen and protected amino and hydroxy groups in R' and R are convertedinto free hydroxy and amino groups. The reaction may be carried out inan alcoholic or aqueous solution of mixed alkali at temperatures betweenroom temperature and the boiling point of the mixture.

In the same manner aldehydes of the formula 1 in which R represents ahydroxy group are obtainable from compounds of the formula 20 (p 2).

Compounds of the formula 1 in which R represents a hydroxy group and Rrepresents a hydromethyl group are obtained by substituting hydroxy forhalogen in a compound of the formula 20 (p 1). The reaction may becarried out with silver hydroxide in an inert solvent such, for example,as dimethylformamide.

The compounds of the formula 20 are obtained by one of theaforementioned cyclization reactions.

Compounds of the formula 1 in which R represents an alkoxy group areobtainable by converting a compound of the formula 18 with analcoholate. The reaction may be carried out in a solvent, preferably analcohol which corresponds to the alcohol from which the alcoholate isderived. Preferably sodium alcoholates are used which are reacted attemperatures between 20C and 80 C.

Compounds of the formula 1 in which R represents a mercapto or analkylthio group are obtainable by reacting a compound of the formula '18 with an alkali hydrosulfide or an alkali mercaptide. The reaction ispreferably carried out with a slight excess of reagent in an alcohol asa solvent at temperatures up to about C.

Compounds of the formula 1 in which R represents a hydroxy group and Rrepresents a carboxylamide group are obtainable by reacting .a compoundof the formula 1 in which R represents an alkoxycarbonyl group withammonia. The reaction may be carried out by shaking the compound of theformula 1 with a con centrated aqueous solution of ammonia attemperature up to about C.

Compounds of the formula 1 in which R, represents an a-hydroxyalkylgroup are obtainable by reducing a compound of the formula 1 in which R,represents an acyl group, a carboxyl group or an alkoxycarbonyl groupwith a hydride; the hydride may be a solution of lithium aluminumhydride or of sodium boron hydride in, for example, tetrahydrofuran ordioxan. The reaction temperature as a rule lies between 0C and theboiling point of the solvent.

The compounds according to the invention may be brought into a formsuitable for administration to the patient by known methods. Thecompounds may be worked up with solid and/or liquid excipients commonlyused in pharmaceutics to form preparations such as powders, tablets,dragees, pills, suppositories, capsules, injection liquids and the like.

The invention will be set out more fully with reference to the followingExamples.

EXAMPLES 1. 3-(ethoxymethyl)-2,3-dihydro-'9-hydroxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethylester.

a. 2-(ethoxymethyl)-7-nitro-l,4-benzodioxan obtained by ethylating2-(hydroxymethyl)-7-nitro1,4- benzoidoxan (Gazz. Chim. Ital. 87,1038-1049 (1957)) with diethylsufate was hydrogenated by means ofapalladium-on-carbon catalyst. The resulting amino was isolated as thehydrochloric acid salt. Melting point C (1 aq.)

1.74 g of this substance was mixed with a solution of 1.45 g of2-(ethoxymethylene)malonic acid diethylester in 20 ml of absoluteethanol. A solution of 0.71 g sodium acetate in 1.2 ml of water wasadded to the mixture, which was then stored at room temperature for 8hours. Subsequently the reaction mixture was concentrated in a vacuumand mixed with diethyl ether. The ethereal solution was washed withwater and then with an aqueous sodium bicarbonate solution, dried oversodium sulfate and concentrated by evaporation. The residue was shakenwith petroluem ether, whereupon 2-{ [(2-ethoxymethylj-1,4-benzodioxan-7-ylamino] methylene} malonic acid diethylester crystallized out. Thesubstance was separated by filtration, washed with petroleum ether anddried in a vacuum. Melting point 6869C.

b. 1.90 g of the obtained substance was dissolved in 25 ml of a mixtureof 26.5 by weight of diphenyl and 73.5% by weight of diphenylether andheated at 250C for 40 minutes. After cooling the superscribed compoundcrystallized out. The substance was separated by filtration, washed withthe mixture of diphenyl and diphenyl-ether, which ethanol and withdiethylether.

7 After recrystallization from ethanol the melting point was 266-268C(with decomposition).

ln analogous manners the following compounds were obtained, which allmelt with decomposition:

2. B-(methoxymethyl)-2,3-dihydro-9-hydroxy-dioxino [2,3-g] quinoline-8carboxylic acid ethylester. Melting point 263265C.

3. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino [2,3-g]quinolinyl-8-methylketone. Melting point 265-267C.

4. 3-(ethocymethyl)-10-chloro-2,3-dihydro-9-hydroxyp-dioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 293295C.

5. 3-(n.propoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 260-262C.

6. 3-(n.butoxymethyl)-2,3-dihydro-9-hydroxy-p dioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 245-248C.

7. 3-(isobutoxymethyl)-2,3-dihydro-9-hydroxyp.dioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 258-262C.

8. 3-(allyloxymethyl)-2,3 dihydro-9-hydroxyp-dioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 254-256C.

9. 3-(cyclopentyloxymethyl)-2,3-dihydro-9-hydroxy-p dioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 257-260C.

l0. 3-(benzyloxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-carboxylic acid ethylester. Melting point 236238C.

l1. 3'[(2-methoxyethoxy)methyl]-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 228-23lC.

l2. dioxino [2,3-g] quinoline-8-carboxylic acid ethylester. Meltingpoint 272-275C.

13. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylamide. Melting point 290-292C.

l4. 3-(ethoxymethyl)-2.3-dihydro-9-hydroxy-pdioxino [2,3-p]quinoline-8-carboxylic acid n.propylester.

a. A solution of 0.15 g of the acid corresponding to the abovementionedester in 2 ml of thionylchloride was boiled for 20 minutes. The excessof thionylchloride was then distilled off in a vacuum. The substanceobtained: 3-(ethoxymethyl)-9-chloro-2,3-dihydro-p dioxino [2,3-g]quinoline-8-carboxylchloride was dissolved in 5 ml of n-propanol. Thesolution was heated at 70C for minutes.

b. A drop of water was added to the solution. The mixture was boiled for90 minutes, concentrated in a vacuum and taken up in 4 ml of water. Theresulting suspension was separated in a centrifuge, the liquid waspoured off and the residue was crystallized from n.propanol. Meltingpoint 270-27 1C with decomposition.

15. 3-(eth'oxymethyl)-2,3dihydro-9-hydroxy-dioxino [2,3-g]quinoline-8-carboxylic acid ethylester.

6.27 ml of absolute ethanol was added drop by drop with vigorousstirring to a cooled mixture of 10.1 g of phosphorus pentoxide and 19.2ml of anhydrous xylene in 10 minutes. The mixture was heated to 70C andmixed with 1 1.4 g of (2-ethoxymethyl)-1,4-benzodi- 0xan-7-ylamino]methylene malonic acid diethylester. The mixture was boiled for 30minutes, then 3-(methylthiomethyl)-2,3-dihydro-9-hydroxy-ppoured inabout 50 ml of water and stirred for 1 hour. The solid substance formedwas filtered off, stirred with a mixture of 25 ml of acetone and 25 mlof diethylether and filtered off again. The substance was crystallizedfrom dimethylformamide, washed with diethylether and dried. Meltingpoint 266-268C with decomposition.

16. 3-( ethoxymethyl )-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid ethylester.

A solution of 3.0 g of (2-ethoxymethyl)-1,4- benzodioxan-7-ylamino]methylene malonic acid diethylester in 30 ml of phosphorus oxychlorideand 3 ml of trie thylamine was boiled for well over 1 hour. The reactionmixture was then concentrated in a vacuum. the concentrate was dissolvedin methylenechloride and the solution was shake with water. Subsequentlysodium carbonate was added until the mixture had become weakly alkaline,after which the layers were separated. The methylenechloride solutionwas washed with water, dried and concentrated. The concentrate waschromatographed on a column of silicagel (eluent methylenechloride).This resulted in 9-chloro-2,3- dihydro-3-(ethoxymethyl)-p-dioxino[2,3-g] quinoline- 8carboxylic acie ethylester having a melting point ofl06108C.

b. A solution of 0.30 g of this chlorine compound in 4 ml of ethanol wasmixed with 0.1 m1 of concentrated hydrochloric acid, after which themixture was boiled under a reflux condenser for 1 /2 hours. The reactionmixture was then concentrated by evaporation in a vacuum and theconcentrate was mixed with 4 ml of water. The resulting precipitate wasseparated off and crystallized from ethanol. Melting point 266-268C withdecomposition.

The following compounds were obtained by analogous methods:

17. 3-(hydroxymethyl)-2,3-dihydro-9-hydroxypdioxino [2,3-g]quinoline-8-carboxylic acid ethylester. Melting point 260T.

18. 3-(ethoxymethyl)-2.3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-methanol. Melting point 278C-279C, partial decompositionbelow the melting point.

19. 3-(ethoxymethyl)-2,3 dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid.

a. 2-([ 2-(ethoxymethyl)-1.4-benzodioxan-7-ylamino])-2-cyanoacrylic acidethyl ester (melting point C-86C) was obtained by reacting 7-amino-2-(ethoxymethyl)-1,4-benzodioxan (Example 1) with 2- cyano-2-ethoxyacrylic acid ethyl ester in boiling ethanol for 1 hour. The product wascyclized in the manner described in Example 1 to form3-(ethoxymethyl)-2,3- dihydro-9-hydroxy-p-dioxino [2,3-g] quinoline-8-carbonitrile. Melting point 248254C with decomposition.

b. A suspension of 2.0 g of this carbonitrile in 50 ml of ln-solution ofcaustic soda was boiled for 6 hours. After cooling, the reaction liquidwas filtered and the filtrate was acidified with 4.5 ml of concentratedhydrochloric acid. The resulting precipitate was sucked off, washed withwater and dried in a vacuum. Melting point 261-262C with decomposition.

20. 3-(Ethoxymethyl)-2,3-dihydro-9-chloro-p-dioxino [2,3-g]quinoline-S-carboxylic acid ethylester a. A solution of 3.0 g of{[2(ethoxymethyl)-l,4- benzodioxan-7-ylamino] methylene malonic aciddiethyl ester in 30 ml of phosphorus oxychloride and 3 ml oftriethylamine was boiled under a reflux condenser for well over 1 hour.Subsequently the reaction mixture was concentrated in a vacuum and theconcentrate was dissolved in methylenchloride and shaken with water. Themixture was mixed with sodium carbonate until it was weakly alkaline,after which the layers were separated. The methylene chloride solutionwas washed with water, dried and concentrated. The concentrate waschromatographed on a silicagel column (eluent methylene chloride). As aresult 9-chloro-2,3-dihydro- 3-(ethoxymethyl)-p-dioxino [2,3-g]quinoline-8- carboxylic acid ethylester was obtained, which has amelting point of l06-l08C.

3-(Ethoxymethyl)-2,3-dihydro-9-methoxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid methylester.

b. The superscribed ester was obtained by reacting 1.2 g of theaforementioned compound in a boiling solution of 0.23 g of sodium in 6ml of methanol for 5 minutes. The substance was isolated byconcentrating the reaction mixture by evaporation in a vacuum, dilutingthe concentrate with water and extracting it with diethylether. Theextract was dried, concentrated, chromatographed (silicagel and gradientelution with benzene/acetone) and crystallized from etherpetroleumether. Melting point 9599C.

21. 9, l -dichloro-3-(ethoxymethyl)-2,3-dihydro-pdioxino [2,3-g]quinoline-S-carboxylic acid ethylester.

g of 10-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-S-carboxylic acid ethylester was mixed with 50 ml ofphosphorus oxychloride and subsequently refluxed for 16 hours. Theexcess of phosphorus oxychloride was then distilled off in a vacuum, andthe residue was mixed with water and methylene chloride. The separatedsolution in methylene chloride was washed thrice with portions of 25 mlof water and then dried over anhydrous sodium sulfate, after which thesolvent was removed by distillation in a vacuum. The crystalline residuewas chromatographed on a column comprising 50 g of silicagel, using amethylene chloride-acetone mixture as the eluent. Melting pointll2-l14C.

22. 10-chloro-3(ethoxymethyl)-2,3-dihydro-9- methoxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethylester.

A mixture of 1 g of 9,l0-dichloro-3-(ethoxymethyl)-2,3-dihydro-p-dioxino [2,3-g] quinoline-8-carboxylic acid ethylester and0.2 g of sodium methylate in 10 ml of methanol was refluxed for minutes.The reaction mixture was then concentrated in a vacuum and theconcentrate was mixed with methylene chloride, hexane and water. Themethylenchloridehexane solution was washed until neutral with water,dried and concentrated. The concentrate was crystallized fromdiethylether. Melting point 85-88C.

23. 3-(ethoxymethyl)-2,3dihydro-9-mercapto-pdioxino [2,3-g]quinoline-8-carboxylic acid ethylester.

A solution of 1.78 g of 9-chloro-3-(ethoxymethyl)- 2,3-dihydro-dioxino[2,3-g] quinoline-8-carboxylic acid ethylester, which had been preparedby a method analogous to that described in Example 20a, in 30 ml ofethanol and 1 ml of methylene chloride was slowly (in about 1 hour)added drop by drop, with stirring, to a solution of 0.74 g of sodiumhydrogen sulfide in 20 ml of 70% ethanol. Stirring was continued forsome time at room temperature. and subsequently the mixture wasconcentrated in a vacuum. The concentrate was mixed withmethylenechloride and water; the layers were separated. The water layerwas washed with methylene chloride. The solution in. methylene chloridewas washed with water, then twice with 2 N solution of caustic soda, andagain with water. The alkaline washing liquid was acidified withconcentrated hydrochloric acid and then extracted 3 times with methylenechloride. The collected extracts were washed with water and, after beingdried and concentrated, chromatographed on a column comprising 25 g ofsilicagel with the use of methylene chloride with from 10% to of acetoneas the eluent (gradient elution). By crystallization of thechromatographed substance from isopropanol the superscribed substancewas obtained. Melting point 199C-202C.

24a. l0-chloro-3-(ethoxyme'thyl)-2,3-dihydro-9 hydroxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid.

4.0 g of the ethyl ester of the above-mentioned acid were dissolved in amixture of 50 ml of ethanol and 50 ml of 2N solution of caustic soda.The solution was then refluxed for 1 hour, cooled, filtered andacidified with concentrated hydrochloric acid to pH 3. The pre cipitateproduced was drawn off, washed respectively with 50 ml of ethanol, 100ml of an ethanol/ether mixture 1:1 and 100 ml of ether, and dried.Melting point 226-267C.

b. lO-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-S-carboxylic acid allyl ester.

A solution of 0.17 g of the carboxylic acid obtained by the methoddescribed in Example 24a in 2 ml of thionyl chloride was boiled withstirring for half an hour. The obtained suspension was then concentratedin a vacuum, mixed with 4 ml of anhydrous allyl alcohol and then heatedto complete solution. After 1 hour 1 drop of water was added. Thesolution was heated at about 90C for half an hour. Then the liquid wasconcentrated by evaporation in a vacuum, and the concentrate was mixedwith water and diethyl ether. The resulting solid substrate as suckedoff and washed with diethyl ether and water to which 2ml of 1.5 Nammonia had been admixed, and again sucked off, washed with 1.5 Nammonia, water and diethyl ether and finally dried in a vacuum. Aftercrystallization from dimethyl formamide the melting point was 263C-265C.

In a manner analogous to that described in Example 24b the followingsubstances were obtained:

25. l0-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-S-carboxylic acid (2-ethoxyethyl) ester.

Melting point 248250C.

26. l0-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-S-carboxylic acid cyclopentyl ester.

Melting point 266C-268C.

27. 1O-chlor0-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-S-carboxylic acid (cyclopropylmethyl) ester.

Melting point 255-257C.

28a. 9-chloro-3-(ethoxymethyl)-2,3-dihydro-10-nitrop-dioxino [2,3-g]quinoline-S-carboxylic acid ethyl ester.

13.2 g of 9'chloro-3-(ethoxyrnethyl)-2,3-dihydro-pdioxino [2,3-g]quinoline-8carboxylic acid ethyl ester was added in batches, withstirring and cooling to from -15C to -l0C, to ml of fuming nitric acid.Stirring at a temperature between l5C and l0C was continued for half anhour. Then the reaction mixture was poured into 1,500 ml of water, andthis mixture was extracted four times with methylene chloride. Theextracts were washed with water until neutral, dired and concentrated.The concentrate was chromatographed on a column comprising 200 g ofsilicagel with the use of methylene chloride containing up to 12% ofacetone as the eluent (gradient elution). Melting point 139.5l40.5C.

b. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-l0- nitro-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester.

3.5 g of the substance obtained by the method described in Example 28awas mixed with 35 ml of acetic acid and 7.0 g of sodium acetate. Themixture was refluxed for 4 hours. After it had been cooled it was mixedwith water; the solid substance produced was sucked off, washed thricewith water, then once with ethanol and finally dried. Melting pointabout 300C with decomposition.

29. -amino-3'(ethoxymethyl)2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester.

A suspension of 3.77 g of 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-l0-nitro-p-dioxino [2,3-g] quinoline-8-carboxylic acidethyl ester, obtained by the method described in Example 28b, in 300 mlof ethanol was added to a prehydrogenated suspension of 0.3 g ofplatinum oxide (Adams catalyst) in ethanol. The suspension washydrogenated at room temperature under a pressure of about 1.1atmosphere until the nitro group had been reduced to an amino group. Thereaction mixture was then heated and filtered while hot. The filtratewas concentrated by evaporation in a vacuum, and the solid residue wascrystallized from absolute ethanol. Melting point 253-256C withdecomposition. 30a. 2 [2-(ethoxymethyl)-5-(trifluoromethyl)-l ,4-ben2odioxan-7-ylamin0j-methylene} malonic acid diethyl ester.

2-benzyloxy-4-nitrophenol was iodinated to 2-benzyloxy-6-iodo-4-nitrophenol of melting point 143145C in the mannerdescribed for an analogous compound in J.Am.Chem. Soc. 75 4290 (1953).This compound was converted with epichlorohydrin into 2-(hydroxymethyl)-5-iodo-7'nitro-1,4-benzodioxane by the method describedin .1.Ned. Chem. 1965 page 455 for an analogous compound. The substanceobtained was ethylated to 2-(ethoxymethyl)-5-iodo-7-nitro-1,4-benzodioxane (melting point of the crude product 90-99C), and this wasconverted with CF J and powdered copper in dimethylformamide into 2-(ethoxymethyl)-7-nitro-5-(trifluoromethyl)-l ,4- benzodioxan by themethod described in Tetrahedron Letters 1969 pages 4095-4096. Thereaction product was hydrogenated by means of a palladium on activecarbon catalyst at room temperature and under a pressure of about 1.1atmospheres to form 7-amino-2-(ethoxymethyl)-5-(trifluoromethyl)-1,4-benzodioxan, which wasimmediately converted with 2-(ethoxymethylene)malonlc acid diethyl esterinto 2- [2- (ethoxymethyl )-5-(trifluoromethyl l ,4-benzodioxzin7-ylaminoI-mcthylenc malonic acid dicthyl ester which had a meltingpoint of 96-98C.

b. 3-(ethoxymethy1)-2,3-dihydro-9-hydroxy-l0-(trifluoromethyl)-p-dioxin0 [2,3-g] quinoline-8- carboxylic acid ethylester.

1.2 g of the compound obtained by the method described in Example (30a)was dissolved in 12 ml of a mixture of 26.5 percent by weight ofdiphenyl and 73.5 percent by weight of diphenyl ether. The solution wasmixed with 0.12 ml of quinoline and subsequently maintained at atemperature between 245C and 250C whilst stirring in a nitrogenatmosphere for 20 minutes. After the reaction mixture had cooled, it wasdiluted with 12 ml of petroleum ether, the crude product crystallizingout. It was sucked off, washed with petroleum ether and subsequently, byselective crystallization from dimethylformamide, separated from thesimultaneously formed byproduct 3-(ethoxymethyl)-2,3- dihydro-S-hydroxy-10-(trifluoromethyl)-p-dioxino [2,3-f] quinoline--carboxylicacid ethyl ester. The superscribed compound had a decomposition point atabout 250C.

31. 3-(ethoxymethyl)-2,3-dihydro-8-( l-hydroxoethyl 9-hydroxy-p-dioxino[2,3-g] quinoline.

A suspension of 0.58 g of 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-dioxino [2,3-g] quinolinyl-8-methyl l etone in 50 mlof methanol was mixed with 0.12 g of sodium boron hydride and themixture was stirred at room temperature for 1.5 hours. Subsequently afurther amount of 0.05 g of sodiumboron hydride was added, the mixturewas stirred for 16 hours, a still further amount of 0.1 g of sodiumboron hydride was added, after which stirring was continued at 50C for0.5 hour. The obtained solution was mixed with 5 ml of water and themixture was concentrated by evaporation in a vacuum. The residual masswas mixed with 30 m1 of water and 30 ml of chloroform, whereupon 3-(ethoxymethyl)-2,3-dihydro-8-( l-hydroxyethyl)-9- hydroxy-p'dioxino[2,3-g] quinoline crystallized out. This was drawn off and washedsuccessively with water, a 1:1 (v/v) acetone-ether mixture and ether.The substance melts at 177-179C with decomposition.

32. 10-(acetylamino)-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g] quinoline-S-carboxylic acid ethyl ester 3 portions of aceticacid anhydride totalling 3 ml were added at intervals of half an hour toa suspension of 0. 1 3 g of 10-amino3-(ethoxymethyl)-2,3-dihydro-9hydroxy-p-dioxino [2,3-g] quinoline-S-carboxylic acid ethyl esterobtained by the method described in Example (29) in 15 m1 of 96%ethanol. Before the last addi tion the reaction mixture was brieflyheated to about 50C, a clear solution being obtained. After the lastaddition the mixture was stirred for another hour and subsequentlyconcentrated by evaporation in a vacuum. The concentrate was mixed withmethylene chloride and water, after which the two layers were separated.The water layer was extracted 2 times with methylene chloride, theentire solution in methylene chloride was then washed thrice with waterand subsequently dried over anhydrous sodium sulfate. Subsequently thesolvent was distilled off in a vacuum. The residue having thesuperscribed structure was not purified any further. 33.3-(ethoxymethyl)-8-ethyl-2,3-dihydro-9-hydroxyp-dioxino [2,3g]quinoline.

A mixture of 0.90 g of 3-(ethoxymethy1)-2,3- dihydro-9-hydroxy-dioxino[2,3-g] quinolyl-ll-methyl kctone, 10 ml of triethylene glycol, 0.50 mlof hydrazine hydrate and 0.40 g of potassium hydroxide was heated at100C for half an hour, the ketone dissolving. The reaction mixture wasslowly heated to C in a flask provided with a short fractionatingcolumn, held 0.29 (on a silicagel plate using the same eluent) wascrystallized from a mixture of acetone and diethyl ether. Melting point166-l68C.

34. 3-(ethoxymethyl)2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-methanol.

0.30 g of 3-(ethoxymethy1)-2,3-dihydro-9-hydroxypdioxino [2,3-g]quinone-8-carboxylic acid ethyl ester was added to a suspension of 0.08g of lithium aluminum hydride in 30 ml of anhydrous tetrahydrofuran. Themixture was refluxed for 1 hour. Then 0.5 ml of water was added drop bydrop, after which the mixture was boiled for a few minutes more. Theresulting precipitate was drawn off, washed with tetrahydrofuran andextracted with 40 ml of absolute ethanol. From the first filtrate andfrom the ethanol extract the solvents were removed by distillation in avacuum. the residue was mixed with ml of water. The solution obtainedwas filtered. 1.8 ml of 1 N acetic acid solution was added to thefiltrate, with the result that the superscribed compound crystallizedout. The substance was drawn off, washed with water and dried in avacuum. Melting point 268C279C (decomposes partly below the meltingpoint).

35. 3-(hydroxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-carboxylic acid ethyl ester.

A warm solution of 0.20 g of 3*(benzy1oxymethy1)-2,3-dihydro-9-hydroxy-p-dioxine [2,3-g] quinoline-8- carboxylic acidethyl ester in 50 ml of ethanol and 0.20 ml of 4,4 N hydrochloric acidwas added to a prehydrated suspension of 0.03 g of platinum oxide(according to Adams) in ethanol. The mixture was hydrogenated at roomtemperature at a pressure of about 1.1 atmosphere until the benzyl grouphad been split off. The catalyst was then removed by filtration. Thefiltrate was concentrated in a vacuum to about g. Subsequently 0.54 mlof 1.62 N ammonia was added, after which the solution was furtherconcentrated. By diluting the concentrate with diethyl ether thesuperscribed hydroxymethyl compound precepitated. The substance wasdrawn off, washed with diethylether and dried. Melting point 260 withdecomposition.

36. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2 ,3-g]quinoline-S-carboxylic acid.

A suspension of 2.86 g of 3-(etl1oxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino [2,3-] quinoline-8- carboxylic acid ethylester in 50 ml of 1 N sodium hydroxide-was boiled for l hour and then,still hot, acidified with 4.5 ml of concentrated hydrochloric acid. As aresult the superscribed compound precipitated in the form of crystals.The substance was drawn off, washed with portions of water totallingabout 50 ml and dried in a vacuum. Melting point 261-262C withdecomposition.

37. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxamide.

A suspension of 0.30 g of 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino [2,3-g] quinoline-8- carboxylic acid ethylester in 10 ml of concentrated ammonia was shaken. in closed tube at 90Cfor 9 hours. The resulting solution was cooled, the tube was opened, thesolution was filtered and the filtrate was concentrated by evaporationin a vacuum to about 5 g. The resulting precipitate was drawn off andthen crystallized from 6 ml of ethanol. Melting point 290299C (withdecomposition).

38. 10-chloro-3-(ethoxyme'thyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-S-carboxylic acid ethyl ester.

A solution of 5 g of 2- [5-chloro-2-(ethoxymethyl)-l,4-benzodioxan-7-ylamino] methylene} malonic acid diethyl esterobtained by a method analogous to that described in Example (la) in 50ml of a mixture comprising 26.5 percent by weight of diphenyl and 73.5percent by weight of diphenyl ether was mixed with 0.5 ml of quinolineand then heated with stirring in a nitrogen atmosphere to 245C in 15minutes. The mixture was stirred in a nitrogen atmosphere at atemperature between 245C and 250C for 45 minutes and then slowly cooledto room temperature. The crystllized substance was drawn off, washedwith 75 ml of a 1:3 ethanol/diethyl ether mixture, dried andcrystallized from dimethyl formamide. Melting point 293295C withdecomposition.

39. 10-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester.

A mixture of l g of 2- [5-ch1oro-2-(ethoxymethyl)-l,4-benzodioxan-7-ylamino] methylene} malonic acid diethyl ester and 10ml of paraffin oil was heated at 240C for 25 minutes. When the mixturehad slowly been cooled and no substance crystallized anymore, 10 ml ofacetone and 5 ml of diethyl ether were added. The solid reaction productwas drawn off and washed with diethyl ether. It was crystallized fromdimethyl formamide. Melting point 293-295C with decomposition.

40. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino-[2,3-g]quinoline-8-carboxylic acid ethyl ester.

A mixture of 0.4 g of 2- [2-(ethoxymethyl)-l,4- benzodioxan-7-y1amino]methylene} malonic acid diethyl ester obtained by the method describedin Example (la) and 2 g of polyphosphoric acid ethyl ester (J. Chem.Soc. 1972 173) was heated at 120C whilst stirring for 1.5 hours. Afterthe reaction mixture had been cooled, it was mixed with 20 ml of waterand then neutralized with sodium bicarbonate. The precipitate formed wasdrawn off and washed with water, with ethanol and with diethyl ether.The substance was further purified by several crystallizations fromdimethylformamide. Melting point 266-268C with decomposition. 41.3-(ethoxymethyl)-2,3dihydro-9-hydroxy-dioxino [2,3-g]quinoline-8-carboxy1ic acid ethyl ester.

a. 6.95 g of 7-amino-2-(ethoxymethyl)-1,4- benzodioxan obtained by themethod described in Example la) was dissolved in 35 ml of water and 2.83ml of concentrated hydrochloric acid, and the mixture was added to asolution of 5.95 chloralhydrate in ml of water, the resulting solutionbeing mixed with a solution of 86.5 g of sodium sulfate in 335 ml ofwater and 7.32 g of hydroxylamine hydrochloride dissolved in 35 ml ofwater. The mixture was heated to boiling temperature in 50 minutes. Itwas then boiled under a reflux condenser for 5 minutes. After themixture had been cooled, it was extracted with methylene chloride. The

extract was washed with water, dried over anhydrous sodium sulfate andconcentratedin a vacuum. The addition of petroleum ether caused2-ethoxymethyl)-7- (2-isonitrosoacetamido)-l ,4-benzodioxan tocrystallize out. Melting point lO3C-l06C.

b. 3.64 g of the compound obtained by the method described in Example(41a) was added in batches whilst stirring to 10 ml of concentratedsulfuric acid heated to 50C. The mixture was heated to 80C and stirredat this temperature for 10 minutes. After the mixture had cooled it waspoured into 120 ml of ice water, whereupon 3-(ethoxymethyl)-p-dioxino[2,3-f] isatin crystallized out. The substance was drawn off, washedfree from acid with water and dried. Melting point 151-l53C.

c. 0.13 g of the substance obtained by the method described in Example(41b) was dissolved in 0.9 ml of 2 N sodium hydroxide. 0.15 ml of 30%hydrogen peroxide solution was added with stirring. After the mixturehad been stirred for some minutes, it was acidified with 2 Nhydrochloric acid and then filtered. The filtrate was evaporated todryness in a vacuum, and the residue was extracted thrice with absoluteethanol. The ethanolic extracts were concentrated by evaporation in avacuum, dissolved in absolute ethanol and again concentrated. Theconcentration was stirred with petroleum ether, with the result that7-amino-2- (ethoxymethyl)-1,4-benzodioxan-o-carboxylic acid crystallizedout. Melting point 124l30C with decomposition. Boiling unter a refluxcondenser with methanolic hydrochloric acid for 1 hour gave thecorresponding methyl ester.

d. A fresh solution of 5 chromatographed g of the sodium salt of formylacetic acid ethyl ester in 20 ml of water was added dropwise withstirring in about minutes to a solution of 3.2 g of the ester obtainedby the method-described in Example (41c) in ml ofwater. After themixture had been stirred for 15 minutes, it was extracted with diethylether. The ethereal extract was dried, concentrated and chromatogoraphedon a silicagel column. 1.00 g of the resulting 7-[2-(ethoxycarboxyl)vinylamino]-2-(ethoxymethy1)-1,4-benzodioxan-o-carboxylic acid methyl ester was dissolved in ml ofabsolute diethyl ether. A solution of 70 mg of sodium in 2 ml absoluteethanol was added dropwise in 2 minutes whilst stirring in a nitrogenatmosphere. After the mixture had been stirred for another 5 minutes,the produced 3-(ethoxymethyl)-2,3- dihydro-9-hydroxy-p-dioxino[2,3-g]quinoline-8-carboxylic acid ethyl ester was isolated by concentrationand crystallization from dimethyl formamide. Melting point 266-268C withdecomposition.

42. 3-(hydroxymethyl)-2,3-dihydro-9-hydroxy pdioxino [2,3-g]quinoline-8-carboxylic acid.

a. 4-amino-2-benzyloxyphenol having a melting point of 106108C wasobtained from the corresponding nitro compound by reduction withpowdered iron and hydrochloric acid according to the method described inHouben-Weyl 11/1 page 399.

b. This substance was condensed with 2- (ethoxymethylene) malonic aciddiethyl ester in the manner described in Example (1) to form 2- {[3-benzyloxy-4-hydroxyanilino]methylene} malonic acid diethyl ester in theform of an 011.

c. 1.74 g of the substance obtained by the method described in Example(42b) was diluted with 17 ml of a mixture of 26.5 percent by weight ofdiphenyl and 73.5 percent by weight of diphenyl ether. The-solution washeated to 250C and held at a temperature between 245C and 250C for 5minutes. Subsequently the solution was slowly cooled. 7-benzyloxy-4,6-dihydroxyquinoline-3-carboxylic acid ethyl ester crystallizing out. Thesubstance was drawn off, washed once with ethanol, thrice with diethylether and dried. Melting point 272-274C.

d. 3.39 g of the compound obtained by the method described in Example42c was mixed with 3 ml of epichlorohydrin and 4 drops of piperidine.The mixture was heated to C in a nitrogen atmosphere whilst stirring.Subsequently 7 ml of epichlorohydrin were added, after which the mixturewas heated at 100C with stirring for 2.5 hours. The reaction mixture wasconcentrated in a vacuum, a dark viscous oil being obtained which mainlyconsisted of 7-benzy1oxy-6-(3-chloro-2-hydroxypropoxy)-4-hydroxyquinoline-3- carboxylic acid ethylester.

e. The product obtained by the method described in Example (42d) wasdissolved in 27 ml of acetic acid. This solution was mixed with 19 ml ofconcentrated hydrochloric acid. This mixture was stirred at 100C in anitrogen atmosphere for 1 hour and then concentrated in a vacuum. Theconcentrate, a dark viscous oil, mainly consisted of6-(3-chloro-2-hydroxy-propoxy)- 4,7-dihydroxyquinoline-3-carboxylic acidethyl ester.

f. The concentrate of obtained by the method described in Example (42c)was mixed with 10 ml of 2N solution of caustic soda and an amount ofwater such as to enable the mixture to be thoroughly stirred. Afterstirring at room temperature for half an hour another portion of 10 mlof 2N solution of caustic soda was added, and the mixture was heated at100C with stirring in a nitrogen atmosphere for 2 hours, whilst afterabout one hour a further portion of 10 ml of 2N solution of caustic sodawas added. After the reaction mix ture had been cooled and filtered, itwas acidified with concentrated hydrochloric acid, 2,3-dihydro-9-hydroxy-3-(hydroxymethyl)-p-dioxino [2,3-g] quinoline-S-carboxylic acidbeing precipitated. The substance was separated off, washed with water,ethanol and diethyl ether and dried. Melting point 230-235C withdecomposition. 43. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-chloro-p-dioxino [2,3-g] quinoline-8-carboxylic acid having a meltingpoint of 266-267C was obtained by the method described in Example (36)from the compound produced by the method described in Example (38).

The following compounds were obtained by methods analogous to thatdescribed in Example (1): 44.3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester. Melting point 250253C. 45.3-(acetoxymethy1)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester. Melting point 271-274C. 46.3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-methyl-p-dioxino [2,3-g]quinoline-8-carboxylic acie ethyl ester. Melting point 269-273C. 47. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxyl 0- methoxy-p-dioxino [2,3g]quinoline-S-carboxylic acid ethyl ester. This compound decomposes above250C.

By methods analogous to that described in Example (14) the followingcompounds were obtained:

17 48. 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-dioxino [2,3-g]quinoline-8-carboxylic acid methyl ester. Melting point 25 7260C. 49.3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-carboxylic acid isobutyl ester. Melting point l66-l67C.

a. Tablet containing 0.05 g of 3-(ethoxymethyl)-9- hydroxyl-nitro-2,S-dihydro-p-dioxino [2,3-g] quinoline-8-carboxylic acid ethylester.

100 g of 3-(ethoxymethyl)-9-hydroxy-l0-nitro-2,3- dihydro-p-dioxino[2,3g] quinoline-8-carboxylic acid ethyl ester was mixed with 190 g ofsecondary calcium phosphate, 90 g of microcrystalline cellulose and 120g of a mixture consisting of 20 parts by weight of maize starch, 32parts by weight of talc and 4 parts by weight of magnesium stearate,until a homogeneous mixture had been obtained. From this mixture tabletswere struck which each had a diameter of 7.5 mm and a weight of 250 mg.

b. Suppository containing 0.05 g of 3- (ethoxymethyl )-9-hydroxy-l0-nitro-2 ,3-dihydro-pdioxino [2,3-g] quinoline-8-carboxylic acidn.propyl ester.

50 mg of 3-(ethoxymethyl)-9-hydroxy-10-nitro-2,3- dihydro-p-dioxino[2,3-g] quinoline-8-carboxylic acid n-propyl ester was mixed with 3 g ofa suppository mass and shaped into the form of a suppository.

c. Injection liquid containing the sodium salt of 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino [2,3- g]quinoline-S-carboxylic acid.

10 g of 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-carboxylic acid were dissolved in an equimolar mount ofdiluted potassium hydroxide. The solution was mixed with a solution of 3g of phenyl and the mixture was diluted with distilled water to a volumeof 1,000 ml and filtered through a bacterial filter, after whichampoules of l or 2 ml each were aseptically filled with the dilutedmixture.

What is claimed is:

1. A compound selected from the group consisting of quinolines of theformula wherein R is hydroxy, R is a substituent selected from the groupconsisting of hydrogen, halogen, trifluromethyl and nitro, R is asubstituent selected from the group consisting of alkoxycarbonyl,alkoxyalkoxycarbonyl, and carboxyl and R is a substituent selected fromthe group consisting of alkoxyalkyl, alkoxyalkoxyalkyl, alkenylalkoxy,cycloalkylalkoxy and cycloalkcnylalkoxy each of up to 6 carbon atoms andhydroxy alkyl of up to 4 carbon atoms, alkali metal salts thereof,tautomers thereof and acid addition salts thereof formed withpharmaceutically acceptable acids with the proviso that the number ofcarbons in the substituents defined by R is at most four when R is asubstituent other than halogen or trifluoromethyl and is six when R ishalogen or trifluromethyl.

2. Quinoline derivatives as claimed in claim 1, in which R represents ahalogen atom.

3. The 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim 1.

4. The 3-(methoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g1]quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim 1.

5. The 3-(ethoxymethyl)-l0-chloro-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g1] quinoline-B-carboxylic acid ethyl ester and salts thereforeformed with pharmaceutically acceptable acids of claim 1.

6. The 3-(n-propoxymethyl)-2,3-dihydro-9-hydroxyp-dioxino [2,3-g1]quinoline-B-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim 1.

7. The 3-(n.butoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim 1.

8. The 3-(isobutoxymethyl)-2,3-dihydro-9-hydroxyp-dioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim 1.

9. The 3-(allyloxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim 1.

10. The 3-(cyclopentyloxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g] quinoline-S-carboxylic acid ethyl ester and salts thereof formedwith pharmaceutically acceptable acids of claim 1.

11. The 3-(benzyloxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

12. The 3-[(2methoxyethoxy)-methyl]-2,3'dihydro-9-hydroxy-p-dioxino[2,3-g] quinoline-S-carboxylic acid ethyl ester andsalts thereof with pharmaceutically acceptable acids of claim 1.

13. The 3-(methylthiomethyl)-2,3-dihydro-9- hydroxy-p-dioxino [2,3-g]quinoline-B-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

14. The 3-(ethoxymethyl)-2,3-dihydro-9'hydroxy-p dioxino [2,3-g]quinoline-S-carboxylic acid, alkali metal salts and salts thereof withpharmaceutically ac ceptable acids of claim 1.

15. The 3-(hydroxymethyl)-2,3-dihydro-9-hydroxyp-dioxino [2,3-g}quinoline-S-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

16. The 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino [2,3-g]quinoline-S-carboxylic acid n.propyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

17. The 3-(ethoxymethyl)-2,3-dlihydro-9-methoxy-pdioxino [2,3-g]quinoline-S-carboxylic acid methyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

18. The 9,10-dichloro-3-(ethoxymethyl)-2,3-dihydro-p-dioxino [2,3-g]quinoline-S-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

19. The l0-chloro-3-(ethoxymethyl)-2,3-dihydro-9- methoxy-p-dioxino[2,3-g] quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

20. The 3-(ethoxymethyl)-2,3-dihydro-9-mercaptop-dioxino [2,3-g]quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

21. The l-chloro-3-(ethoxymethyl)-2,3-dihydr0-9- hydroxy-p-dioxino[2,3-glquinoline-8-carboxylic acid allyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

22. The l0-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g] quinoline-8-carboxylic acid (2-ethoxymethyl) ester and saltsthereof with pharmaceutically acceptable acids of claim 1.

23. The lO-chloro-3-(etlioxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g] quinoline-8-carboxylic acid cyclopentyl ester and salts thereofwith pharmaceutically acceptable acids of claim 1.

24. The lO-chloro-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g] quinoline-8-carboxylic acid (cyclopropylmethyl) ester and saltsthereof with pharmaceutically acceptable acids of claim 1.

25. The 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy- IO-nitro-p-dioxino[2,3-g] quinoline-S-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

26. The l0-amino-3-(ethoxymethyl)-2,3-dihydro-9- hydroxy-p-dioxino[2,3-g] quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

27. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxylO-(tri-fluoromethyl)-p-dioxino[2,3-g] quinoline-8- carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

28. The 3-(hydroxymethyl)-2,3-dihydro-9-hydroxyp-dioxino [2,3-g]quinoline-8-carboxylic acid, alkali metal salts and salts thereof withpharmaceutically acceptable acids of claim 1.

29. The 3-(ethoxymethyl)-2,3-dihydro-9-hydroxylO-chloro-p-dioxino[2,3-g] quinoline-8-carboxylic acid, alkali metal salts and saltsthereof with pharmaceutically acceptable acids of claim 1.

30. The 3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-pdioxino {2,3-g]quinoline-S-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

31. The 3-(acetoxymethyl)-2,3-dihydro-9-hydroxyp-dioxino [2,3-g]quinoline-S-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.

acids of claim 1.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF QUINOLINES OF THEFORMULA
 2. Quinoline derivatives as claimed in claim 1, in which R3represents a halogen atom.
 3. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino ( 2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 4. The3-(methoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino ( 2,3-g))quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 5. The3-(ethoxymethyl)-10-chloro-2,3-dihydro-9-hydroxy-p-dioxino ( 2,3-g))quinoline-8-carboxylic acid ethyl ester and salts therefore formed withpharmaceutically acceptable acids of claim
 1. 6. The3-(n-propoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino ( 2, 3-g))quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 7. The3-(n.butoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 8. The3-(isobutoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 9. The3-(allyloxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 10. The3-(cyclopentyloxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino 2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof formed withpharmaceutically acceptable acids of claim
 1. 11. The3-(benzyloxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2, 3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 12. The3-((2-methoxyethoxy)-methyl)-2,3-dihydro-9-hydroxy-p-dioxino(2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 13. The3-(methylthiomethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2, 3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 14. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid, alkali metal salts and salts thereof withpharmaceutically acceptable acids of claim
 1. 15. The3-(hydroxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 16. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid n.propyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 17. The3-(ethoxymethyl)-2,3-dihydro-9-methoxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid methyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 18. The9,10-dichloro-3-(ethoxymethyl)-2,3-dihydro-p-dioxino (2, 3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 19. The10-chloro-3-(ethoxymethyl)-2,3-dihydro-9-methoxy-p-dioxino (2,3-g)quinoliNe-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 20. The3-(ethoxymethyl)-2,3-dihydro-9-mercapto-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 21. The10-chloro-3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino(2,3-g)quinoline-8-carboxylic acid allyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 22. The10-chloro-3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid (2-ethoxymethyl) ester and salts thereofwith pharmaceutically acceptable acids of claim
 1. 23. The10-chloro-3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid cyclopentyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 24. The10-chloro-3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid (cyclopropylmethyl) ester and salts thereofwith pharmaceutically acceptable acids of claim
 1. 25. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-nitro-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 26. The10-amino-3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 27. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-(tri-fluoromethyl)-p-dioxino(2,3-g) quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 28. The3-(hydroxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid, alkali metal salts and salts thereof withpharmaceutically acceptable acids of claim
 1. 29. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-chloro-p-dioxino (2,3-g)quinoline-8-carboxylic acid, alkali metal salts and salts thereof withpharmaceutically acceptable acids of claim
 30. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 31. The3-(acetoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 32. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-methyl-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 33. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-10-methoxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid ethyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 34. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxylic acid methyl ester and salts thereof withpharmaceutically acceptable acids of claim
 1. 35. The3-(ethoxymethyl)-2,3-dihydro-9-hydroxy-p-dioxino (2,3-g)quinoline-8-carboxyl acid isobutyl ester and salts thereof withpharmaceutically acceptable acids of claim 1.